Are the current preclinical models adequate to evaluate CAR-T cell therapy in pediatric high-grade gliomas?

Pediatric high-grade gliomas (pHGGs) are aggressive childhood brain tumors with 5-year survival rates below 20%. They are distinct from adult HGGs (aHGGs) and are driven by histone mutations, disrupted developmental programs, and an immunologically restrained tumor microenvironment (TME). While chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, its application to pHGGs faces significant challenges for clinical translation. This perspective aims to provide a comprehensive overview of pHGG biology, CAR-T cell therapy principles, and current preclinical models, highlighting translational gaps and strategies to bridge them. We first examined the molecular and cellular landscape of pHGGs, emphasizing the unique features that shape responsiveness to antigen-directed therapies, detailing the mechanisms of CAR-T therapy, successes in hematological malignancies, and specific challenges in central nervous system (CNS) tumors. Next, we critically discussed the preclinical platforms, ranging from traditional 2D cultures to advanced patient-derived 3D systems and in vivo mouse models. While these systems provide mechanistic insights and enable assessment of CAR-T efficacy, none fully replicate the pediatric TME or developmental context, contributing to the recurrent gap between preclinical efficacy and clinical outcomes. This perspective highlights current knowledge, translational limitations, and future strategies to enhance CAR-T research in pediatric neuro-oncology.